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Published ahead of print on May 11, 2007, doi:10.1165/rcmb.2006-0455OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 309-321, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0455OC

Genomic Profile of Matrix and Vasculature Remodeling in TGF-{alpha}–Induced Pulmonary Fibrosis

William D. Hardie, Thomas R. Korfhagen, Maureen A. Sartor, Adrienne Prestridge, Mario Medvedovic, Timothy D. Le Cras, Machiko Ikegami, Scott C. Wesselkamper, Cynthia Davidson, Maggie Dietsch, William Nichols, Jeffrey A. Whitsett and George D. Leikauf

Divisions of Pulmonary Medicine, Pulmonary Biology, and Human Genetics, Cincinnati Children's Hospital Medical Center; Center of Environmental Genetics and Environmental Health, University of Cincinnati School of Medicine, Cincinnati, Ohio; and Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Correspondence and requests for reprints should be addressed to William D. Hardie, M.D., Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229. E-mail: william.hardie{at}cchmc.org

Expression of transforming growth factor {alpha} (TGF-{alpha}) in the respiratory epithelium of transgenic mice caused pulmonary fibrosis, cachexia, pulmonary hypertension, and altered lung function. To identify genes and molecular pathways mediating lung remodeling, mRNA microarray analysis was performed at multiple times after TGF-{alpha} expression and revealed changes consistent with a role for TGF-{alpha} in the regulation of extracellular matrix and vasculogenesis. Transcripts for extracellular matrix proteins were augmented along with transcripts for genes previously identified to have roles in pulmonary fibrosis, including tenascin C, osteopontin, and serine (or cysteine) peptidase inhibitor, clade F, member 1. Transcripts regulating vascular processes including endothelin receptor type B, endothelial-specific receptor tyrosine kinase, and caveolin, caveolae protein 1 were decreased. When TGF-{alpha} expression was no longer induced, lung remodeling partially reversed and lung function and pulmonary hypertension normalized. Transcripts increased during resolution included midkine, matrix metalloproteinase 2, and hemolytic complement. Hierarchical clustering revealed that genes regulated by TGF-{alpha} were similar to those altered in the lungs of patients with idiopathic pulmonary fibrosis. These studies support a role for epithelial cell–derived TGF-{alpha} in the regulation of processes that alter the airway and vascular architecture and function.

Key Words: epidermal growth factor receptor • idiopathic pulmonary fibrosis • vasculogenesis • angiogenesis • interstitial lung disease


CLINICAL RELEVANCE

This study demonstrates that pulmonary fibrosis induced through epidermal growth factor receptor (EGFR) activation is reversible. Targeting the EGFR may prove to be a target to reverse fibrotic disease.

 



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